title: Targeting ligand-operated chaperone sigma-1 receptors in the treatment of neuropsychiatric disorders.
abstract: BACKGROUND
  Current drugs for the treatment of psychiatric or neurodegenerative disorders have limitations. Psychotherapeutic drugs such as typical and atypical antipsychotics, tricyclic antidepressants and selective monoamine reuptake inhibitors, aim to normalize the hyper- or hypo-neurotransmission of monoaminergic systems. Despite their contribution to the outcomes of psychiatric patients, these agents often exert severe side effects and require chronic treatments to promote amelioration of symptoms. Drugs available for the treatment of neurodegenerative disorders are severely limited.
  
  
  METHODS
  Recent evidence that has shed light on sigma-1 receptor ligands, which may serve as a new class of antidepressants or neuroprotective agents. Sigma-1 receptors are novel ligand-operated molecular chaperones regulating signal transduction, ER stress, cellular redox, cellular survival and synaptogenesis. Selective sigma-1 receptor ligands exert rapid antidepressant-like, anxiolytic, antinociceptive and robust neuroprotective actions in preclinical studies. Recent studies that suggest that reactive oxygen species might play a role as signal integrators downstream of Sig-1Rs are also covered.
  
  
  CONCLUSIONS
  The advances in sigma receptor research in the last decade have begun to elucidate the intracellular signal cascades upstream and downstream of sigma-1 receptors. The novel ligand-operated properties of the sigma-1 receptor chaperone may enable interventions by which stress-related cellular systems can be pharmacologically controlled.
authors.affiliation: National Institute on Drug Abuse, National Institutes of Health-Cellular Stress Signaling Unit, Integrative Neuroscience Branch, Baltimore, MD 21224, USA. Thayashi@intra.nida.nih.gov
authors.forename: Teruo
authors.initials: T
authors.lastname: Hayashi
authors.forename: Shang-Yi
authors.initials: SY
authors.lastname: Tsai
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Mori
authors.forename: Michiko
authors.initials: M
authors.lastname: Fujimoto
authors.forename: Tsung-Ping
authors.initials: TP
authors.lastname: Su
mesh_terms: D000437:Alcoholism / Q000188:drug therapy; D000818:Animals; D000928:Antidepressive Agents; D003863:Depression / Q000188:drug therapy; D004721:Endoplasmic Reticulum / Q000502:physiology; D006801:Humans; D008024:Ligands; D001523:Mental Disorders / Q000188:drug therapy*; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D009473:Neuronal Plasticity; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D017480:Receptors, sigma / Q000819:agonists* / Q000502:physiology; D012559:Schizophrenia / Q000188:drug therapy; D013569:Synapses / Q000502:physiology; D000097605:Sigma-1 Receptor
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor